Patients with HER2+ metastatic breast cancer are often treated with a multitude of therapies in the metastatic setting, and additional strategies to prolong responses to anti-HER2 therapies are needed. Preclinical evidence suggests synergy between cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors and anti-HER2 therapies. We conducted a phase 1b study of ribociclib and ado-trastuzumab emtansine (T-DM1) in patients with advanced/metastatic HER2-positive breast cancer previously treated with trastuzumab and a taxane in any setting, with four or fewer prior lines of therapy in the metastatic setting. A standard 3 + 3 dose-escalation design was used to evaluate various doses of ribociclib in combination with T-DM1, starting at 300 mg. The primary objective was to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) of ribociclib in combination with T-DM1. A total of 12 patients were enrolled. During dose-escalation, patients received doses of ribociclib of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 3). No dose-limiting toxicities were observed. The majority of toxicities were Grade 1 and 2, and the most common Grade 3 toxicities were neutropenia (33%), leukopenia (33%), and anemia (25%). After a median follow-up of 12.4 months, the median PFS was 10.4 months (95% confidence interval, 2.7–19.3). Based on the pharmacokinetic analysis, adverse events, and dose reductions, 400 mg was determined to be the RP2D for ribociclib given on days 8–21 of a 21-day cycle with T-DM1.

HER2+ 转移性乳腺癌患者通常在转移性环境中接受多种疗法，因此需要额外的策略来延长对抗 HER2 疗法的反应。临床前证据表明细胞周期蛋白依赖性激酶 4 和 6（CDK 4/6）抑制剂与抗 HER2 疗法之间存在协同作用。我们对 ribociclib 和 ado-trastuzumab emtansine (T-DM1) 对先前在任何情况下接受过曲妥珠单抗和紫杉类治疗的晚期/转移性 HER2 阳性乳腺癌患者进行了一项 1b 期研究，在此之前接受过四线或更少的治疗转移设置。标准的 3 + 3 剂量递增设计用于评估各种剂量的 ribociclib 与 T-DM1 的组合，起始剂量为 300 mg。主要目标是确定 ribociclib 与 T-DM1 组合的最大耐受剂量和/或推荐的 2 期剂量（RP2D）。共招募了 12 名患者。在剂量递增期间，患者接受了 300 mg ribociclib（n  = 3)、400 毫克 ( n  = 3)、500 毫克 ( n  = 3) 和 600 毫克 ( n  = 3)。未观察到剂量限制性毒性。大多数毒性为 1 级和 2 级，最常见的 3 级毒性为中性粒细胞减少症 (33%)、白细胞减少症 (33%) 和贫血 (25%)。中位随访 12.4 个月后，中位 PFS 为 10.4 个月（95% 置信区间，2.7-19.3）。根据药代动力学分析、不良事件和剂量减少，400 mg 被确定为在 21 天周期的第 8-21 天使用 T-DM1 给予 ribociclib 的 RP2D。